Chromatin-associated OGT promotes hepatocellular carcinoma malignancy via activating ZNF263 [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA918970 | ENA |
REPOSITORIES: ENA
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Project description:The reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Despite the dysregulation of the sole enzyme O-GlcNAc transferase (OGT), is showed to associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and achieves transcriptional functions remain unclear. Here, we demonstrate that the elevated OGT increases HCC proliferation and metastasis by orchestrating the transcription of numerous malignant regulators in vitro and in vivo. Diverse transcriptional regulators are recruited by OGT in HCC cells with progressive malignancy, which shapes the genome-wide OGT chromatin cis-elements occupation. Further, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcriptomics. We reveal that the O-GlcNAcylation site Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters and OGT facilitated HCC the malignant phenotypes. Our data establish the importance of aberrant OGT and ZNF263 O-GlcNAcylation in HCC malignant progression, and represents the pursuit of OGT as a target for HCC therapy.
2023-01-09 | GSE222281 | GEO
Project description:The reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Despite the dysregulation of the sole enzyme O-GlcNAc transferase (OGT), is showed to associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and achieves transcriptional functions remain unclear. Here, we demonstrate that the elevated OGT increases HCC proliferation and metastasis by orchestrating the transcription of numerous malignant regulators in vitro and in vivo. Diverse transcriptional regulators are recruited by OGT in HCC cells with progressive malignancy, which shapes the genome-wide OGT chromatin cis-elements occupation. Further, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcriptomics. We reveal that the O-GlcNAcylation site Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters and OGT facilitated HCC the malignant phenotypes. Our data establish the importance of aberrant OGT and ZNF263 O-GlcNAcylation in HCC malignant progression, and represents the pursuit of OGT as a target for HCC therapy.
2023-01-09 | GSE222280 | GEO
Project description:Chromatin-associated OGT promotes hepatocellular carcinoma malignancy via activating ZNF263.
| PRJNA918965 | ENA
Project description:Chromatin-associated OGT promotes hepatocellular carcinoma malignancy via activating ZNF263 [RNA-seq]
| PRJNA918969 | ENA
Project description:OGT, the only facilitator which attaches the monosaccharide to many oncogenic factors or tumor suppressors, has been suggested to play an influential role in tumorigenesis and metastasis of HCC. OGT interactome analyses indicates that disordered OGT may serve as a hub protein to activate the building of aberrant transcriptional regulatory complexes, supporting that this unique enzyme is an essential regulator in tumor progression. However, the function and related mechanisms by which OGT triggers HCC malignancy are still largely unknown
2023-01-12 | PXD039365 |
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-01-09 | GSE222282 | GEO
Project description:Half of all human transcription factors use C2H2 zinc finger domains to specify site-specific DNA binding and yet very little is known about their role in gene regulation. Based on in vitro studies, a zinc finger code has been developed that predicts a binding motif for a particular zinc finger factor (ZNF). However, very few studies have performed genome-wide analyses of ZNF binding patterns and thus it is not clear if the binding code developed in vitro will be useful for identifying target genes of a particular ZNF. We performed genome-wide ChIP-seq for ZNF263, a C2H2 ZNF that contains 9 finger domains, a KRAB repression domain, and a SCAN domain and identified more than 5000 binding sites in K562 cells. Our results suggest that ZNF263 binds to a 24 nt site which differs from the motif predicted by the zinc finger code in several positions. Interestingly, many of the ZNF263 binding sites are located within the transcribed region of the target gene. Although ZNFs containing a KRAB domain are thought to function mainly as transcriptional repressors, many of the ZNF263 target genes are expressed at high levels. To address the biological role of ZNF263, we identified genes whose expression was altered by treatment of cells with ZNF263-specific siRNAs. Our results suggest that ZNF263 can have both positive and negative effects on transcriptional regulation of its target genes. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Examination of ZNF263 ChIP-seq in K562 cells.
2009-12-03 | E-GEOD-19235 | biostudies-arrayexpress
Project description:EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical successes in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and gain resistance. Here, we identified transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumor specimens. Exogenous expression of ZNF263 improved the initial response of cells and delayed the formation of persister cells with osimertinib. We elaborated that ZNF263 bound and recruited DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 could also interact with nuclear EGFR (nEGFR), impairing the nEGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also made tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or AAV-mediated plasmid delivery of ZNF263 synergistically suppressed tumor growth and regrowth with osimertinib in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.
2024-01-23 | GSE253742 | GEO
Project description:EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical successes in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and gain resistance. Here, we identified transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumor specimens. Exogenous expression of ZNF263 improved the initial response of cells and delayed the formation of persister cells with osimertinib. We elaborated that ZNF263 bound and recruited DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 could also interact with nuclear EGFR (nEGFR), impairing the nEGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also made tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or AAV-mediated plasmid delivery of ZNF263 synergistically suppressed tumor growth and regrowth with osimertinib in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.
2024-01-23 | GSE253741 | GEO
Project description:Ovarian high-grade serous carcinoma (HGSC) accounts for the majority of deaths caused by epithelial ovarian cancer. The precise molecular changes attributable for the pathogenesis of HGSC are still largely unknown. TRAF4 has been identified to be up-regulated in some cancers. However, the association between TRAF4 and the malignancy of HGSC has not been elucidated before. In this study, we aim to explore the prognostic value and function of TRAF4 in HGSC. The results of immunohistochemistry in 174 cases of HGSC showed that high expression of TRAF4 was significantly associated with a shorter overall survival (p=0.005) and recurrence-free survival (p=0.003) in HGSC. Knock-down of TRAF4 inhibited the malignancy of ovarian cancer cells, and over-expression of TRAF4 increased cell malignancy both in vitro and in vivo. Moreover, mechanism studies demonstrated that TRAF4 promoted cell malignancy by activating YAP pathway in HGSC. In conclusion, TRAF4 could be a prognostic biomarker for HGSC and increase HGSC cell malignancy by activating YAP pathway, which may serve as a potential therapeutic target for HGSC.
2022-05-15 | GSE202840 | GEO